We propose to investigate two potential mechanisms of host defense in leishmaniasis, an important protozoal disease caused by the growth of the parasite within host macrophages. We will utilize an in vitro system comprised of pathogenic species of parasites and mouse leukocytes. These studies are designed to provide the scientific basis for subsequent field studies of the clinical immunology of the disease, with an eye toward the eventual development of immunoprophylactic or immunotherapeutic methods. We will compare the ability of lymphokine obtained from two sources to activate macrophages to kill intracellular Leishmania, lymphokine from PPD-triggered BOG-sensitized lymphocytes and specifically-sensitized lymphocytes triggered with leishmanial antigens. The ability of pharmacologic triggers of macrophage activation (muramyl dipeptide, phorbol myristate acetate, and endotoxin) to induce leishmanicidal mechanisms in inflammatory cells will be studied in a similar manner. The role of superoxide and other toxic oxygen intermediates in the leishmanicidal pathway will be explored by the addition of scavengers of active oxygen to infected macrophages stimulated with lymphokines or activators. Cell-mediated cytotoxicity will be studied by co-cultivating leishmania-sensitized spleen or lymph node leukocytes with syngeneic leishmania-infected macrophages or free parasites, in the presence or absense or anti-leishmanial antibody. Release of 51Cr or 3H-uracil from infected cells or free parasites, cell uptake of trypan blue, ultrastructural changes, and inhibition of parasite multiplication will be used as evidence of cytotoxicity.